PROJECT SUMMARY/ABSTRACT Chronic viral infections and the co-infections they foster are among the greatest health concerns worldwide. Although their linkage is clear, it is much less clear how one pathogen alters the immune environment to foster another. T cells are critical both to control chronic virus infections and to correctly orchestrate de novo immune responses against co-infecting pathogens. Thus, we surmised that if the immune environment during chronic virus infection altered the ability to appropriately mount T cell responses, that it would jointly and simultaneously affect the chronic infection and susceptibility / severity of secondary infections. The goal of this proposal is to investigate how chronic inflammation and the evolving host:pathogen interactions as viral persistence progresses alters immunity to co-infecting pathogens. To achieve this goal, we have developed a novel mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection and Mycobacterium tuberculosis (Mtb) co-infection. Our preliminary data demonstrate that in the presence of established chronic viral infection, Mtb specific immune responses are delayed, redirected and Mtb replication increased. In the current proposal, we will mechanistically investigate how the modulation of the immune response by the chronic virus spreads to delay acquired Mtb-specific immunity and determine the mechanistic basis through which the altered T cell immunity enhances Mtb disease progression. We will then examine the reciprocal relationship between established Mtb infection and chronic viral co-infection to understand how they comparatively impact the ability to generate and sustain simultaneous immune responses and modulate disease course. The experiments outlined in this proposal will establish important biologic principles and provide a new mechanistic link between the host:pathogen interactions that foster viral persistence with those that enhance susceptibility to and severity of secondary infections. Ultimately, the mechanisms and paradigms we reveal have the potential to lead to new strategies to treat chronic viral infections and the co-infections that plague them.